FSU Grand Rounds12/13/2018

Funded by NIDA, NIAAA

National Survey on Drug Use & Health (NSDUH), 2013

NSDUH, 2013

NSDUH, 2015

2015

NSDUH, 2017

2015

2017

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10

2002 2014

PregnantNonpregnant

PAST MONTH MARIJUANA USE AMONG PREGNANT AND NONPREGNANT WOMEN

Brown et al., JAMA 2017

Perc

ent

0

2

4

6

8

10

12

14

16

12-17 yrs 18-25 yrs ≥ 25 yrs

PAST MONTH MARIJUANA USE AMONG PREGNANT WOMEN BY AGE

Volkow et al., Annals Int Med 2017

Perc

ent

INCREASING POTENCY OF MARIJUANA

INCREASING POTENCY OF MARIJUANA

2012

LEGALIZATION OF MARIJUANA

cnn.com

wcvb.com

INCREASING LEGALIZATION OF MARIJUANA

INCREASING LEGALIZATION OF MARIJUANA

CHALLENGES IN STUDYING PRENATAL MARIJUANA EXPOSURE

• Theoretical model• Assessment of exposure• Assessment of outcomes• Assessment of covariates• Evaluating prenatal vs. current environmental

influences

CHALLENGES IN STUDYING PRENATAL MARIJUANA EXPOSURE

• Theoretical model• Assessment of exposure• Assessment of outcomes• Assessment of covariates• Evaluating prenatal vs. current environmental

influences

HOW TO MEASURE DRUG USE?

PARAMETERS FOR MEASURINGSUBSTANCE USE

• Quantity• Frequency• Duration

HOW MUCH ALCOHOL IS IN A DRINK?

12 oz beer = 5 oz wine = shot of liquor

Each contains 0.5 oz of alcoholNIAAA

WHAT IS MARIJUANA?

Cannabis Sativa plant

500+ compounds; 100+ cannabinoids

Mechoulam & Hanuš, 2000

Main psychoactive ingredient is ∆9-tetrahydrocannabinol (∆9-THC)

JOINTS

BLUNTS

CIGARS, CIGARILLOS

PIPES, BONGS

Image courtesy of the Weed Street Journal

MARIJUANA WAX

MARIJUANA INTOXICATION

Initially, increase in arousal, excitement, vasodilation, tachycardia, heightened senses

Later, euphoria, sedation, relaxation; at high doses, perceptual changes, paranoia, anxiety attacks

Post-intoxication involves low energy, decreased motivation, binge eating, sedation

Side effects include memory impairments, impaired motor coordination, poor judgment, erratic behavior, reduced reaction time

NEUROBIOLOGY OF MARIJUANA

Guzman (2003), Nat. Reviews Cancer

Endocannabinoids bind to cannabinoid receptors (CB1 and CB2)

CB1 receptors are GPCRs and are Gi/ocoupled

Activation of CB1 typically decreases vesicular neurotransmitter release

NEUROBIOLOGY OF MARIJUANA

Elliot Gardner - Neuroscience Letters, 1991, 129: 1872-79

DA

in N

ucle

us A

ccum

bens

CANNABINOID EFFECTS ON DOPAMINE TRANSPORT

Transl Psychiatry. 2016 May; 6(5): e809

Stanwood group has described protective effects of GLP-1 receptor agonists on cocaine reward.

This is due to GLP-1 receptors blocking the endocannabinoid 2-AG, which then retrogradely alter the trafficking dynamics of thedopamine transporter (the substrate for cocaine).

ENDOCANNABINOIDS AND NEURODEVELOPMENT

In human, CB1 receptors are detectable by week 14 of gestation

Many possiblemechanisms

through which drugs can alter fetal

neurodevelopment

ANIMAL MODELS OF PRENATALMARIJUANA / THC / CANNABINOIDS

• Generally speaking, the animal literature has been poorly developed!

• Multiple doses, duration, and routes of administration have been used with little consistency.

• Nevertheless, several recent studies of note.

Impaired performance on a skill pellet-reaching task

Transiently altered CB1 receptors during prenatal development

Deficits restored by normalization of CB1 receptors on excitatory neurons!

Reduced hippocampal CCK-INT number and complexity

Compromised CCK-INT-mediated feedforward and feedback inhibition

Altered socialbehavior

Pittsburgh Maternal Health Practices & Child Development Project Cohorts

Alcohol Use During Pregnancy

NIAAAN. Day

Prenatal MarijuanaExposure

NIDAN. Day

Teenage PrenatalTobacco UseNIAAA/NIDAM. Cornelius

Prenatal CocaineUse

NIDAG. Richardson

Core Data SetsInstrumentsPersonnelAnalyses

PRENATAL PHASES4th prenatal month 7th prenatal month 24-48 hrs post-delivery

1st trimester 2nd trimester 3rd trimester

STUDY DESIGN

4TH PRENATAL MONTH 1982-19857TH PRENATAL MONTH

DELIVERY (N = 763 combined cohort)8 MONTHS18 MONTHS

10 YEARS

16 YEARS

3 YEARS6 YEARS

14 YEARS

22 YEARS

METHODS OF DETECTION

• Biological markers

• Interviews

• Self-report questionnaires

BIOLOGICAL MARKERS

Window of detection varies with:

• Type of assay

• Drug

• Chronicity of use

DETECTION OF MARIJUANA USE

DETECTION OF MARIJUANA USE

• Substantial evidence of greater detection of marijuana use by self-report/interview methods than by biological assays

Fendrich et al., 2004; Gray et al., 2010; Richardson et al., 2006

DETECTION OF MARIJUANA USE

Positive urine screen, reported use on interview:

95%

Reported use on interview, negative urine screen:

40%

Usual

Marijuana 37%

Cocaine 47%

IMPORTANCE OF QUESTION FORMAT

Richardson, Huestis, Day, 2006

Usual Maximum Minimum

Marijuana 37% 45% 17%

Cocaine 47% 50% 3%

IMPORTANCE OF QUESTION FORMAT

Richardson, Huestis, Day, 2006

PATTERN OF MATERNAL MARIJUANA USE

0102030405060708090

100

Yearprior

1st trim. 3rd trim. 18 mos 6 yrs 14 yrs 22 yrs

PER

CEN

T

None: 0 joints/day Light: <1 joint/day Heavy: 1+ joints/day

PATTERN OF MATERNAL ALCOHOL USE

0

10

20

30

40

50

60

70

80

Yearprior

1st trim. 3rd trim. 18 mos 6 yrs 14 yrs 22 yrs

PER

CEN

T

None: 0 drinks/day Light: <1 drink/day Heavy: 1+ drinks/day_

PATTERN OF MATERNAL TOBACCO USE

0

10

20

30

40

50

60

1st trim. 3rd trim. 18 mos 6 yrs 14 yrs 22 yrs

PER

CEN

T

None: 0 cigarettes/day Light: < 1 pack/day Heavy: 1+ packs/day_

WHAT IS ASSOCIATED WITH PRENATAL MARIJUANA USE?

CHARACTERISTICS ASSOCIATED WITH 1ST

TRIMESTER MARIJUANA USE

No Use Heavy Use* Significance

Maternal age 22.9 23.2 ns(yrs)

Education (yrs) 12.0 11.8 ns% Caucasian 53.8 22.3 p < .01% Married 37.6 18.4 p < .01Family income 56.1 71.3 p < .05(% < $400/month)

*≥ 1 joint/dayDay et al., 1991

USE OF OTHER SUBSTANCES BY FIRST TRIMESTER MARIJUANA USE

0102030405060708090

Alcohol Tobacco Other Drugs

No PMEHeavy PME**≥1 joint/day

PER

CEN

T

1st trimester drug use

EFFECTS OF PRENATAL MARIJUANAMATERNAL HEALTH COHORT

Birth 3 years 6 years 10 years 14 years 22 years

GROWTH ___________________________________________________________________

BEHAVIOR________________________________________________________________

COGNITIVE

EFFECTS ON COGNITION

RELATION BETWEEN PME & 6 YEAR IQ

80

85

90

95

100

105

Overall IQ ST Memory Verbal

No PMEHeavy PME**≥1 joint/day

Stan

ford

-Bin

et S

core

s

Goldschmidt et al., 2008

Nomarijuana

use

Lighta

marijuana use

Heavyb

marijuana use

Significance

No adjustments 95.9 93.6 89.0 .001

Goldschmidt et al., 2004a < 1 joint/day; b ≥ 1 joint/day

IMPORTANCE OF CONTROL OF COVARIATES10-year PIAT reading comprehension

Nomarijuana

use

Lighta

marijuana use

Heavyb

marijuana use

Significance

No adjustments 95.9 93.6 89.0 .001

Adjust for:Home environment (HOME)

95.6 93.7 90.2 .01

Goldschmidt et al., 2004a < 1 joint/day; b ≥ 1 joint/day

IMPORTANCE OF CONTROL OF COVARIATES10-year PIAT reading comprehension

Nomarijuana

use

Lighta

marijuana use

Heavyb

marijuana use

Significance

No adjustments 95.9 93.6 89.0 .001

Adjust for:Home environment (HOME)

95.6 93.7 90.2 .01

HOME, education 95.5 93.9 90.1 .01

Goldschmidt et al., 2004a < 1 joint/day; b ≥ 1 joint/day

IMPORTANCE OF CONTROL OF COVARIATES10-year PIAT reading comprehension

Nomarijuana

use

Lighta

marijuana use

Heavyb

marijuana use

Significance

No adjustments 95.9 93.6 89.0 .001

Adjust for:Home environment (HOME)

95.6 93.7 90.2 .01

HOME, education 95.5 93.9 90.1 .01

HOME, education, race

95.1 94.1 91.5 ns

Goldschmidt et al., 2004a < 1 joint/day; b ≥ 1 joint/day

IMPORTANCE OF CONTROL OF COVARIATES10-year PIAT reading comprehension

EFFECTS ON BEHAVIOR

RELATION BETWEEN PME & 10 YEAR BEHAVIOR

0

5

10

15

20

25

30

Delinquent Aggressive

No PMEHeavy PME*

*≥1 joint/day

Perc

ent a

bove

bor

derli

ne

clin

ical

cut

off

Teacher Reported Behavior Goldschmidt et al., 2000

OFFSPRING SUBSTANCE USE ACROSS TIME

0102030405060708090

100

10 years 14 years 22 years

AlcoholTobaccoMarijuana

% use

P < .001

Sonon et al., 2015

RELATION BETWEEN PME & 22 YEAR OFFSPRING MARIJUANA USE

0

10

20

30

40

50

60

70

No PME Any PME

No use

≥ 3 times/wk%

use at 22 yrs

RELATION BETWEEN PME & PSYCHOTIC SYMPTOMS AT 22 YEARS

0

10

20

30

40

50

60

70

PS = 0 PS ≥ 3

No PMEHeavy PME*

*≥1 joint/day

Perc

ent

Psychotic symptoms Day et al., 2015

Adolescent marijuana exposure increases susceptibility to develop psychosis and other neuropsychiatric conditions. Even earlier exposures may do the same (or worse?).

EFFECTS OF PRENATAL MARIJUANAMATERNAL HEALTH COHORT

Birth 3 years 6 years 10 years 14 years 22 years

GROWTH length -- -- -- -- --___________________________________________________________________

BEHAVIOR sleep changes impulsivity activity, delinquency, marijuana use,inattention, marijuana use psychotic sx,impulsivity, arrestsdelinquency,depression

_________________________________________________________________

COGNITIVE IQ, IQ, memory,memory memory achievement achievement

• Effects of prenatal marijuana exposure on

behavior and cognition consistent across phases

(and studies)

• Increased risk of marijuana use in offspring

• Pattern of effects consistent with teratologic model

and mechanisms

CONCLUSIONS

IMPLICATIONS

• Different types/patterns of prenatal marijuana use

• Co-use of marijuana and tobacco is common

• Consider other characteristics associated with prenatal drug use

• Non-judgmental communication is important

• Understand woman’s belief system

MATERNAL HEALTH PROJECT

3 years 6 years 10 years 14 years

Overall IQ- Short term memory- Verbal

Day et al., 1994

Overall IQ- Short-term memory-Verbal-Quantitative

Goldschmidt et al., 2008

Achievement:- Reading- Spelling

Memory – overall;- visual

Goldschmidt et al., 2004;Richardson et al., 2002

Achievement:- Reading- Total

Goldschmidt et al., 2012

EFFECTS OF PRENATAL MARIJUANA EXPOSURE ON COGNITIVE DOMAINS

EFFECTS OF PRENATAL MARIJUANA EXPOSURE ON BEHAVIOR

6 years 10 years 14 years 22 years

Impulsivity Inattention ImpulsivityActivity

Psychoticsymptoms

Delinquency Delinquency Maladaptive adult roles

Depression Marijuana use Marijuana use

Leech et al., 1999 Goldschmidt et al., 2000;Gray et al., 2005

Day et al., 2006, 2011 Day et al., 2015;Goldschmidt et al., 2016;Sonon et al., 2015